Acyloxy and hydroxy substituted quinolizines



United States Patent 3,378,560 ACYLOXY AND HYDROXY SUBSTITUTEDQUENOLIZINES Richard E. Brown, Hanover, and Robert I. Meitzer, Rockaway,Ni, assignors to Warner-Lambert Pharmaceutic'al Company, Morris Plains,N.I., a corporation of Delaware No Drawing. Filed July 21, 1965, Ser.No. 473,810 Claims. (Cl. 260-286) This invention relates to novelsubstituted acyloxy and hydroxy substituted quinolizines of the formula:

wherein R and R each represent hydrogen, hyd-roxy, lower alkoxy of 1 to6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy and the likeor R and R taken together form a methylenedioxy group; R representshydrogen or lower alkyl of 1 to 6 carbon atoms such as methyl, ethyl,propyl, isopropyl and the like; R may be hydroxy; acyloxy of 1 to 6carbon atoms such as acetoxy, formyloxy, propyloxy and the like; orketo; R represents hydrogen, carboxy or a carboxy derivative such as-CO0R in which R; may be lower alkyl of 1 to 6 carbon atoms or in whichR; may be hydrogen or lower alkyl of 1 to 6 carbon atoms; R may behydrogen, hydroxy, acyloxy of 1 to 6 carbon atoms or R and R takentogether form a keto or a cyclic ketal group and n is an integer of 1 to2.

The symbols R R R R R R and n as used hereinafter have the same meaningas defined above.

The compounds of this invention are assigned the following numberingsystem when 11:1

and when n=2 This invention also includes within its scope the novelprocess for the production of the above compounds. The compounds of thisinvention exhibit significant pharmacological activity and are useful ascardio-vascular agents or anti-inflammatory agents. They also exhibitsteroidal activity. In use these compounds are combined with an inertpharmaceutical carrier to form dosage forms such as tablets, capsules,suspensions, elixirs and the like. They may also be combined with othertherapeutic agents such as antibiotics, for example, the penicillins,the tetracyclines, analgesics, for example, namol xenyrate, steroids,for example, ,B-methasone, cardio-vascular agents, for example,pentaerythritoltetranitrate, glyceryl trinitrate and the like andtranquilizers such as 1,4-benzodiazepines.

In addition, these compounds are important intermediates for theproduction of compounds of the formula:

vention, the above products are prepared by treating a starting materialof the formula:

with an appropriate nucleophilic agent in a suitable solvent such asacetone, water or acetic acid. In the above Formula III, X is halogenand these starting materials are prepared in accordance with the methoddescribed III in application Ser. No. 348,286 filed Feb. 18, 1964, nowPatent No. 3,294,801. Starting materials for the preparation of III aregenerally described and claimed in our cpending application, Ser. No.248,872, filed J an. 3, 1963, now Patent No. 3,341,543. The startingmaterials for III are prepared from R and R substitutedphenylalkylamines of the general Formula A below and substitutedketoacids of the general Formula B below in accordance with the processdescribed in our copending application Ser. No. 318,190, filed Oct. 23,1963, now Patent No. 3,301,864. The R, and R substitutedphenylalkylamines such as 3,4-diethoxyphenylethylamines are well-knowncompounds which are described in the literature, for example in ChemicalAbstracts, vol. 56, page 10006g, and by Ide et al., in I.A.C.S., vol.59, page 726 (1937). The ketoacids of Formula B are prepared accordingto the process described in our copending application Ser. No. 310,146,filed Sept. 19, 1963, now Patent No. 3,301,889, using 2-R-cycloalkane-1,3-diones as starting material. Such 2-R-cy-cloal'kane-1,3-diones are well-known in the art and may be preparedaccording to the procedure of Panouse and Sannie published in Bull Soc.Chim. France, 1955, page 1036. See also H. Smith, JCS. 1964, page 4472.

ZiQ I The keto lactam C is then cyclized with phosphorous oxychlorideand further treated in accordance with the process set forth in saidcopending application. Nucleophilic reagents suitable for use in thisreaction are, for example, the alkali and alkaline earth metal salts oforganic acids such as potassium acetate, lithium formate, sodiumpropionate and the like. Also of use are salts derived by dissolvingorganic bases in organic acids as, r

for example, triethyl ammonium acetate and the like, or silver nitratewhich is particularly useful for the preparation of 11 or 12 ketosubstituted quinolizines. Compound II may then be readily converted tocompound I employing suitable reducing agents such as gaseous hydrogenin the presence of palladium on carbon.

In order to further illustrate this invention, the following examplesare given:

Example 1.-2,3,3a,5,6,1l,12,l2a-octahydro-8-methoxy- 11 acetoxy 1Hbenz[a] cyclopenta[f]quinoliziniurn perchlorate A solution of 2.0 g. of2,3,3a,5,6,11,12,12a-octahydro- S-methoxy-ll-bromo 1Hbenz[a]cyclopenta[f]quinoliziniurn bromide in ml. of acetic acid isadded to a solution of 1 g. of fused potassium acetate in 10 m1. ofacetic acid. The mixture is allowed to stand for 18 hours at ambienttemperature. It is then filtered and concentrated to an oil. The oil isdissolved in water and the solution filtered. The filtrate is treatedwith 10% perchloric acid solution until precipitation is complete. Thegummy precipitate is recrystallized from ethanol to give2,3,3a,5,6,11,12,12a-octahydro 8 methoxy-ll-acetoxy- 1Hbenz[a]cyclopenta[f]quinolizinium perchlorate as yellow crystals, M.P.160-3 C.

4 Example 2.2,3,3a,5,6,11,12,12a-octahydr0-8-rnethoxyll-acetoxy 12amethyl-l-carbethoxy-lH-benz[a]cyclopenta[f] quinolizinium perchlorate Bythe same reaction as described in Example 1, 2.0 g. of2,3,3a,5,6,11,12,12a octahydro 8 methoxy 11- bromo12a-methyl-l-carbethoxy-lH-benz[a]cyclopenta [f]quinoliziniumperchlorate gives2,3,3a,5,6,11,12,12aoctahydro-8-methoxy-11-acetoxy-12a-methyl-1carbethoxy-lH benz[a]cyclopenta[f]quinolizinium perchlorate as whitecrystals, M.P. 173-5 C. after recrystallization from ethanol.

Example 3.-2,3,3a,5,6,11,12,12a-octahydro-8-mcthoxy ll-keto 1Hbenz[a]cyclopenta[f]quinolizinium perchlorate A solution of 6.9 g. ofsilver nitrate in 500 ml. of acetonitrile is added to a solution of 8.3g. of 2,3,3a,5,6,11,12, 12a-octahydro-8-methoxy 11 bromo-1H-benz[a]cyclopenta[f]quinolizinium bromide in 500 ml. acetonitrile. The mixture isstirred at ambient temperature for 18 hours. The precipitated silversalts are filtered and the filtrate is concentrated to an oil. The oilis dissolved in water, filtered, and to the filtrate is added a 10%solution of perchloric acid. The gummy precipitate is recrystallizedfrom methanol to give 2,3,3a,5,6,11,12,12aoctahydro-S-methoxy 11keto-1H-benz[a]cyclopenta [f]quinoliziniurn perchlorate as yellowcrystals, MP. 182-4 C.

Example 4.2,3,3a,5,6,11,12,l2a-octahydro-8-methoxy- 11-keto-12a-methyl 1carbethoxy-lH-benz[a]cyclopenta[f] quinolizinium perchlorate By the samereaction as described in Example 3, 76 g. of 2,3,3a,5,6,11,12,l2aoctahydro 8 methoxy 11- bromo-12a-methyl-l-carbethoxy-lI-Ibenz[a]cyclopenta [f]quinoliziniurn bromide gives2,3,3a,5,6,11,12,12aoctahydro-S-methoxy-l1-ket0-12a methyl-l-carbethoxy-1H benz[a]cyclopenta[f]quinolizinium perchlorate as yellow crystals,M.P. 168-7 1 C. after recrystallization from methanol.

Example 5.--2,3,3a,5,6,11,12,12a octahydro-S-methoxy- 11 keto12a-methyl-l-hydroxy-l-carbomethoxy-lH--benz[a]cyclopenta[f]quinolizinium perchlorate By the same reaction asdescribed in Example 3, 66.1 g. of 2,3,3a,5,6,11,12,12aoctahydro-8-methoxy-ll-bromo- 12a-methyl 1hydroxy-l-carbomethoxy-1Hbenz[a1cyclopenta[f]quinolizinium bromide gives2,3,3a,5,6,ll,12, l2a-octahydro 8 methoxy-l1-keto-12a-methyl-1-hydroxy 1carbomethoxy-1H-benz[a]cyclopenta[f]quinolizinium perchlorate as yellowcrystals, MP. 140-3 C. after recrystalization from methanol.

Example 6.-1,2,3,3a,5,6,l0b,11,12,12a decahydro 8- rnethoxy-ll-acetoxybenz a] cyclopentaljf] quinolizine To a solution of 0.5 g. of2,3,3a,5,6,11,12,12a-octahydro-8-methoxy-11-acetoxy-1II-benz[a]cyclopental[flquinoliziniumperchlorate, prepared according to Example 1, in 50 ml. of methanol isadded in portions over 1 hour a total of 0.5 g. of potassiumborohydride. The mixture is evaporated to a gum, and the residue ispartitioned with water and ether. The ether phase is dried andconcentrated to give 1,2,3,3a,5,6,10b,11,12,12a decahydro-S-niethoxy-ll-acetoxy benz[a]cyclopenta[f]quinolizine as a mixture ofisomers about positions 10b and 11, MB. 13641 C.

Example 7.-1,2,3,3a,5,6,10b,11,12,12a decahydro 8-methoxy-l1-hydroxy-benz[a]cyclopenta[f]quinolizine A solution of 1.5 g.of l,2,3,3a,5,6,10b,11,12,1221-dccahydro-8-methoxy-l l-acetoxybenz[a]cyclopentflflquiuolizinc in 20 ml. of ethanol is diluted with 50ml. or" 5% sodium hydroxide solution. The mixture is heated to C. for /2hour. It is then concentrated to remove most of the ethanol, and theoily precipitate is extracted with ether. The ether is dried andconcentrated to give 1,2,3, 3a,5,6,10b,11,12,12adecahydro-8-methoxy-ll-hydroxybenz[a] cyclopental[f] quinolizine as awhite solid mixture of isomers, M.P. 130*-50 C. The mixture of isomersmay be separated by chromatography on alumina. Elution with 1% EtOH inether affords two pure isomers, M.P. 171 C. for the first eluted isomer,and M.P. 190-1" C. for the second eluted isomer. Elution with 3% ethanolin ether aliords the third isomer, M.P. 1778 C.

Example 8.1,2,3,3a,5,6,l0b,11,12,12a decahydro 8- methoxy-ll-hydroxy-benz[a] cyclopenta[f] quinolizine Example9.--1,2,3,3a,5,6,10b,11,12,12a decahydro 8-methoxy-l1-hydroxy-12a-methyl 1 carbethoxybenz [a] cyclopenta [f]quinolizine By the same reaction as described in Example 8, 17.1 g. of2,3,3a,5,6,11,12,l2a-octahydro-8-methoxy-ll-keto- 12amethyl-l-carbethoxy-1H-benz[a]cyclopenta[a]quinolizinium perchlorategives 1,2,3,3a,5,6,1'0b,11,12,12adecahydro-8-methoxy-1l-hydroxyIZa-methyI-I-carbethoxy-benz[a]cyclopenta[flquinolizine as whitecrystals, M.P. 148-9 C. after recrystalization from ethyl acetate.

Example 10.1,2,3,3a,5,6,10b,11,12,12a decahydro-8-methoxy-12a-methyl-1,11-dihydroxy l-carbomethoxybenz [a] cyclopenta[f]quinolizine In the same way as described in Example 8, 12 g. of2,3,3a,5,6,11,12,12a-octahydro-8-methoxy 12amethyll-hydroxy-l-carbomethoxy 11keto-1H-benz[a]cyclopenta[f]quinolizinium perchlorate gives1,2,3,3a,5,-6,10b, 11,12,12a-decahydro 8methoxy-12a-methyl-l,ll-dihydroxy-1-carbomethoxy benz[a] cyclopenta[f]quinolizine as white crystals, M.P. 154 C. after recrystallization fromethyl acetate.

Example 11.-1,2,3,3a,5,6,10b,11,12,12a decahydro-S-,methoxy-l1-hydroxy-12a-methyl 1 carbethoxy-benz [a ]cyclopenta [f]quinolizine f A solution of 1.0 g. of 2,3,3a,5,6,11,12,12a-octahydro-S-methoXy-ll-keto-lZa-methyl 1 carbethoxy-lH-benz[a]cyclopenta[flquinolizinium perchlorate in 200 ml. of methanolcontaining 0.3 g. of palladium on carbon catalyst is hydrogenated atambient temperature and 50 p.s.i. until hydrogen absorption is complete,usually about /2 hour. The catalyst is filtered and the filtrateconcentrated to 5 ml. volume. The slurry is cooled overnight in an icechest and filtered to give a small crop of unchanged startingperchlorate. The filtrate is concentrated to dryness and the residue ispartitioned between ether and 5% sodium hydroxide solution. The ethersolution is dried and concentrated to give an oil. The oil isrecrystallized from ethyl acetate to give1,2,3,3a,5,6,10b,11,12,12a-decahydro- 8-methoxy-11-hydroxy-12a-methyl 1carbethoxy-benz [a]cyclopenta[f]quinolizine, M.P. 132-7 C.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of, our invention.

Having described our invention, what we desire to secure by LettersPatent is:

We claim:

1. A member selected from the grou consisting of compounds of theformula:

Rel R5 R I in which R, and R are each a member of the group consistingof. hydrogen, hydroxy, lower alkoxy and R and R taken together form amethylenedioxy group; R is a member selected from the group consistingof hydrogen, methyl or ethyl, R is a member selected from the groupconsisting of hydroxy, lower alkanoyloxy and keto; R is a memberselected from the group consisting of hydrogen, carboxy and and s inwhich R is a member selected from the group consisting of hydrogen andlower alkyl; R is a member of the group consisting of hydrogen, hydroxy,lower alkanoyloxy and R and R taken together form a cyclic ketal groupand ketone.

2. 2,3,3a,5,6,11,12,12a octahydro-B-methoxy-l1-acetoxy-lH-benz a]cyclopenta [f] quinolizinium perchlorate.

3. 2,3,3a,5,6,11,12,12a octahydro-B-methoxy-ll-acetoxy 12a methyl1-carbethoxy-1H-benz[a]cyclopenta- [f quinolizinium perchlorate.

4. 2,3,3a,5,6,11,12,l2a octahydro-8-methoxy-1l-ketolH-benz acyclopenta[f] quinolizinium perchlorate.

5. 2,3,3a,5,6,11,12,12a octahydro-8-methoxy-1l-keto- 12a methyl 1carbethoxy-lH-benz[a]cyclopenta-[f] quinolizinium perchlorate.

6. 2,3,3a,5,6,11,12,12a octahydro-S-methoxy-ll-keto- 12a methyl 1hydroxy-1-carbomethoxy-lH-benz[a] cyclopenta [f] quinoliziniumperchlorate.

7. 1,2,3,3a,5,6,10b,11,12,12a decahydro 8-methoxy- 1 1-acetoxy-benz a]cyclopenta [f] quinolizine.

8. 1,2,3,3a,5,6,10b,11,12,12a decah'ydro S-methoxyl l-hydroxy-benz [a]cyclopenta f] quinolizine.

9. 1,2,3,3a,5,6,10b,11,12,12a decahydro S-methoxy- 11hydroxy-12a-methyl-l-carbethoxy-benz[aJcyclopenta- [f quinolizine.

10. 1,2,3,3a,5,6,10b,11,12,12a decahydro 8-methoxy- 12a methyl1,1l-dihydroxy-1-carbomethoxybenz[a] cyclopenta[f]quinolizine.

References Cited Osborne et al.: J. Pharm. and Exptl Therap., vol. 147,pp. 212-224, 1965.

Cram et al.: Organic Chemistry, McG-raW-Hill, 1959, p. 188.

Djerrassi: Steroidal Reactions, Holden-Day, 1963, p. 558.

NICHOLAS S. RIZZO, Primary Examiner. ALEX MAZEL, Examiner.

D. DAUS, Assistant Examiner.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA: